Activation of AMP-activated protein kinase stimulates Na+,K +-ATPase activity in skeletal muscle cells
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Contraction stimulates Na+,K+-ATPase and AMP-activated protein kinase(AMPK)activity in skeletal muscle. Whether AMPK activation affects Na+,K+-ATPase activity in skeletal muscle remains to be determined. Short term stimulation of rat L6 myotubes with the AMPK activator 5-aminoimidazole-4-carboxamide- 1-β-D-ribofuranoside (AICAR), activates AMPK andpromotes translocation of the Na+,K +-ATPase α1-subunit to the plasma membrane and increases Na+,K+-ATPase activity as assessed by ouabain-sensitive 86Rb+uptake. Cyanide-induced artificial anoxia, as well as a direct AMPK activator (A-769662) also increase AMPK phosphorylation and Na+,K+-ATPase activity. Thus, different stimuli that target AMPK concomitantly increase Na+,K +-ATPase activity. The effect of AICAR on Na+,K +-ATPase in L6 myotubes was attenuated by Compound C, an AMPK inhibitor, as well as siRNA-mediated AMPK silencing. The effects of AICAR on Na+,K+-ATPase were completely abolished in cultured primary mouse muscle cells lacking AMPK+-subunits. AMPK stimulation leads to Na+,K+-ATPase α1-subunit dephosphorylation at Ser18, which may prevent endocytosis of the sodium pump. AICAR stimulation leads to methylationanddephosphorylation of the catalytic subunit of the protein phosphatase (PP) 2A in L6 myotubes. Moreover, AICAR-triggered dephosphorylation of the Na+,K+-ATPase was prevented in L6 myotubes deficient in PP2A-specific protein phosphatase methylesterase-1 (PME-1), indicating a role for the PP2A•PME-1 complex in AMPK-mediated regulation of Na+,K+-ATPase. Thus contrary to the common paradigm, we report AMPK-dependent activation of an energy-consuming ion pumping process. This activation may be a potential mechanism by which exercise and metabolic stress activate the sodium pump in skeletal muscle.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Number of pages||13|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 2012 Jul 6|